JPH107572A - Tumor necrosis factor production inhibitor - Google Patents

Abstract

(57) [Problem] To provide a tumor necrosis factor production or secretion inhibitor. SOLUTION: The general formula: (In the formula, R ₁ represents a halogen atom or a group -A-R _10. A represents a single bond, an oxygen atom or an NH group, and R ₁₀ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl. Represents a group, an acyl group, a substituted acyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group or a monocyclic heterocyclic group, wherein R ₂ and R ₃ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group , A substituted alkyl group, an alkoxy group, a phenyl group, a substituted phenyl group,
Acyl group, substituted acyl group, acyloxy group, nitro group,
It may represent an amino group, a substituted amino group or a cyano group, or R ₂ and R ₃ may be bonded to each other to form a cyclic structure. R ₄ represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a phenyl group, a substituted phenyl group, a cycloalkyl group, an alkoxy group, a phenyloxy group, a substituted phenyloxy group or a heterocyclic group. An inhibitor of tumor necrosis factor production or secretion containing the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a TNF production or secretion inhibitor containing a pyridazine derivative or a salt thereof.

[0002]

2. Description of the Related Art Tumor necrosis factor
, Hereinafter abbreviated as TNF. ) Is a peptide consisting of 157 amino acids and having a molecular weight of about 17000, and is one of cytokines produced from various cells including macrophages. Although TNF was initially found to be a cytokine with tumor-damaging effects, subsequent studies have shown that its effects extend to many normal cells besides tumor cells.
It has been revealed that it shows various activities. For example,
Inhibition of lipoprotein lipase activity of fat globules, expression of HLA antigen on vascular endothelial cells and fibroblasts, production of interleukin-1 in fibroblasts or macrophages, activation of tumor-toxic macrophages, suppression of CFU, fibroblasts Production of colony stimulating factor of endothelial cells and certain tumor cells, inhibition and absorption of cartilage proteoglycan synthesis, activation of neutrophils and generation of superoxide, production of procoagulant factor of vascular endothelial cells, fibroblasts Proliferation, changes in skeletal myofascial potential, production of interferon-β2 in fibroblasts,
Injury to vascular endothelial cells is one such phenomenon. Recently, it has been widely understood as a cytokine involved in host defense through an inflammatory immune response (Vassalli, P., Ann. Re.
v. Immunol., 10 , 411 (1992)).

On the other hand, it has also been revealed that continuous or overproduction of TNF, on the other hand, has a severe effect on normal cells and causes various disease states. For example, TNF
Has been reported to be the same substance as cachectin, a inducer of cachexia in cancer and infectious diseases, which promotes catabolic metabolism in the whole body and causes extreme exhaustion (B. Beutle
r, D. Greenwald, JD. Hulmes et al., Nature, 316,
552 (1985), Masakami Kawakami, Biochemistry, 59 , 1244 (1987)).
TNF is also one of the causes of sepsis, and an inhibitory effect has been observed in experiments using anti-TNF antibodies (Starnes, HF Jr., Pearce, MK, Tewari,
A., Yim, JH, Zou, JC., Abrams, JS, J. Immun
ol. 145, 4185 (1990), Beutler, B., Milsark, IW,
Cerami, AC, Science, 229, 869 (1985), Hinshaw,
LB, Tekamp-olson, P., Chang, ACK et al, Ci
rc. Shock, 30 , 279 (1990)).

[0004] In rheumatoid arthritis, an increase in TNF has been observed in synovial fluid and blood of patients (Tett).
a, C., Camussi, G., Modena, V., Vittorio, CD, B
aglioni, C., Ann. Rheum. Dis., 49 , 665 (1990)),
Its remarkable effect has been observed in clinical experiments using anti-TNF antibodies (Elliott, MJ Maini, RN, Feldman,
M., Kalden, JR, Antoni, C., Smolen, JS, Lee
b, B., Breedveld, FC, Macfarlane, JD, Biji,
H., Woody, JN, Lancet, 344, 1105 (1994), Elliott,
MJ Maini, RN, Feldman, M., Charles, P., Bi
ji, H., Woody, JN, Lancet, 344, 1125 (1994), EC
C. Rankin, EHS Choy, D. Kassimos, GH Pana
yi, British J. Rheum., 34 , 334 (1995)). further,
Regarding inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, a relationship between the disease state and TNF has been suggested (Murch, S.,
Walker-Smith, JA, Arch.Dis.Child, 66 , 561 (19
91), Maeda Masahiro, Gastrointestinal tract and immunity, 22 , 111 (1989)), and its effect has been recognized in clinical experiments using anti-TNF antibodies (Hendrik, M. Van Dullemen, Sander, JH Van De).
venter, Daan, W. Hommes, Hannie, A. Bul, Jaap, Jan
sen, Guido, NJ Tytgat, and James, Woody, GASTRO
ENTEROLOGY 109, 129 (1995)).

[0005] In addition, osteoarthritis (Venn, G., Nietfe
ld, JJ, Duits, AJ, Brennan, FM, Arner,
E., Covington, M., Billingham, MEJ, Hardingha
m, TE, Arthritis Rheum., 36 (6), 819 (1993)), Kawasaki disease (Matsubara, T., Furukawa, S., Yubuta, K., Cli)
n. Immunol. Immunopathol., 56 , 29 (1990)), multiple sclerosis (Sharief, MK, Hentges, R., N. Engl. J. M.
ed., 325 ( 7), 467 (1991)), Behcet's disease (Akogl
u, T., Direskeneli, H., Yazici, H., Lawrence, R.,
J. Rheumatol., 17 , 1107 (1990)), systemic lupus erythematosus (SLE) (Maury, CPJ, Teppo, AM., Arthritis
Rheum., 32 , 146 (1989)), rejection during bone marrow transplantation (Gv
HD) (Nestel, FP, Price, KS, Seemeyer, T.
A., Lapp, WS, J. Exp. Med., 175, 405 (1992)),
Multiple organ failure (Toshifumi Fujiwara, Masashu Kawakami, clinician, 17 (10), 20
06 (1991)), malaria (Grau, GE, Fajardo, LF,
Piguet, PF, et al, Science, 237, 1210 (1987)
), Acquired immunodeficiency syndrome (AIDS) (Masawa Kawakami, Kuniyasu Hayata, Medical Immunology, 20 , 615 (1990), Dezube,
BJ, Pardee, AB, et al, J. Acquir. Immune Defi
c. Syndr., 5, 1099 (1992)), meningitis (Waage, A., Ha
lstensen, A., Espevik, T., Lancet I, 355 (1987)
), Hepatitis (Kanzo Kanno, liver, 33 , 213 (1992)), type II diabetes (Hotamisligil, GS, Shargill, NS, Spiegel)
man, BM, Science, 259, 87 (1993)) and the like.

As described above, it has been found that excessive TNF production sometimes has an adverse effect on living organisms, and research and development of TNF inhibitors that can be used as therapeutic agents for such pathological conditions are desired. Pentoxifylline having a methylxanthine skeleton is known as a compound having a TNF inhibitory action, for example. This compound also has a lethal protective activity in endotoxin shock model mice, improves mood in severe pulmonary tuberculosis patients, shows weight loss suppression, improves mood in cancer patients, shows weight loss inhibitory effect,
Inhibitory effect in experimental allergic encephalitis model, or
It has been reported that HIV-1 inhibits replication (Zabel,
P., Schade, FU, Schlaak, M., Immunobiol., 18
7 , 447-463 (1993), Dezube, BJ, Pardee, AB et
al., Cancer Immuno. Immunother., 36 , 57-60 (1993),
Nataf, S., Louboutin, JP, Chabannes, D., Feve,
JR, Muller, JY, Acta Neurol. Scand., 38, 97
-99 (1993), Fazely, F., Dezube, BJ, Allen-Ryan,
J., Pardee, AB, Ruprecht, RM, Blood, 77, 16
53-1656 (1991)). In addition, as a compound or factor exhibiting a TNF inhibitory action, conventionally, glucocorticoids, protease inhibitors, phospholipase A2 inhibitors, lipoxygenase inhibitors, PAF (platelet aggregation factor) antagonists, radical scavengers, prostaglandin F2 or I2,
Anti-TNF antibodies and the like are known. However, these compounds have side effects due to a wide variety of pharmacological actions, and their use is problematic, and the development of highly safe drugs by a new mechanism is desired.

[0007]

DISCLOSURE OF THE INVENTION The present invention relates to diseases in which TNF is considered to be involved in the onset of TNF through its TNF production or secretion inhibitory action, such as cachexia, septic shock, multiple organ failure, rheumatoid arthritis. , Inflammatory bowel disease, multiple sclerosis, osteoarthritis, Behcet's disease,
Systemic lupus erythematosus (SLE), rejection during bone marrow transplantation (Gv
HD), malaria, acquired immunodeficiency syndrome (AIDS), meningitis, hepatitis, type II diabetes and the like.

[0008]

Means for Solving the Problems The present inventors have found that a compound represented by the following general formula (1) has a TNF inhibitory action, and have completed the present invention. That is, the present invention relates to the general formula (1)

Embedded image

(Wherein R ₁ is a halogen atom or a group -A
- representing the R _10. A represents a single bond, an oxygen atom or an NH group, and R ₁₀ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an acyl group, a substituted acyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group. Or a monocyclic heterocyclic group. R ₂ and R ₃ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group,
Represents a substituted alkyl group, an alkoxy group, a phenyl group, a substituted phenyl group, an acyl group, a substituted acyl group, an acyloxy group, a nitro group, an amino group, a substituted amino group or a cyano group, or R ₂ and R ₃ are bonded to each other To form an annular structure. R ₄ is an alkyl group, a substituted alkyl group,
Tumor necrosis containing a pyridazine derivative represented by alkenyl group, substituted alkenyl group, phenyl group, substituted phenyl group, cycloalkyl group, alkoxy group, phenyloxy group, substituted phenyloxy group or heterocyclic group) or a salt thereof It relates to a factor production or secretion inhibitor.

[0010] The present invention is further the general formula (1) (wherein, .A and R ₁₀ R ₁ represents a halogen atom or a group -A- R ₁₀ is, A represents a single bond, R ₁₀ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an acyl group, a substituted acyl group, or a heterocyclic group of a cycloalkyl group or a monocyclic, a represents an oxygen atom, R ₁₀ is Represents a hydrogen atom, an alkenyl group, a substituted alkenyl group, an acyl group, a substituted acyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group or a monocyclic heterocyclic group, A represents an NH group, and R ₁₀ represents a hydrogen atom , An alkyl group,
Represents a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an acyl group, a substituted acyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group or a monocyclic heterocyclic group.
R ₂ and R ₃ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group, a substituted alkyl group, an alkoxy group, a phenyl group, a substituted phenyl group, an acyl group, a substituted acyl group, an acyloxy group, a nitro group, an amino group. Represents a group, substituted amino group or cyano group, or R ₂ and R ₃ are bonded to each other, together with the carbon atom to which they are bonded, to form a 5- to 7-membered saturated or unsaturated hydrocarbon ring or Forms a nitrogen-containing heterocycle. R ₄ is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a phenyl group,
Represents a substituted phenyl group, a cycloalkyl group, an alkoxy group, a phenyloxy group, a substituted phenyloxy group or a heterocyclic group) or a salt thereof.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The functional groups in the present invention will be described below. Examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, dimethylethyl , Pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,
2-dimethylpropyl, hexyl, 1-methylpentyl, 2-
Methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, and the like.

The substituent in the substituted alkyl group includes a hydroxyl group, a halogen atom, an alkoxy group, a carboxyl group,
Amino group, substituted amino group, phenyl group, substituted phenyl group, acyl group, acyloxy group, substituted carbamoyl group,
And alkoxycarbonyl groups.Examples of the substituted alkyl group include hydroxymethyl, chloromethyl, bromomethyl, trichloromethyl, 2-hydroxyethyl, 2-aminoethyl, 3-hydroxypropyl, benzyl, carboxymethyl, and methoxycarbonyl. Methyl, ethoxycarbonylmethyl, 4-methoxyphenylmethyl,
And 4-hydroxyphenylmethyl.

Examples of the alkenyl group include alkenyl groups having 2 to 7 carbon atoms, and specific examples include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, -Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl , 5-heptenyl, 6-heptenyl, 2-methyl-1-propenyl, 3-ethyl-2-pentenyl, 3,4-dimethyl-1-hexenyl, 2-methyl-1-heptenyl and the like.

Examples of the substituent in the substituted alkenyl group include the same examples as in the case of the substituted alkyl group, and specific examples of the substituted alkenyl group include 2-chloro-1-propenyl, 3-hydroxy-1-propenyl, 2-chloro-1-butenyl, 4-methoxy-2-butenyl, 4-phenyl-3-butenyl, 3-bromo-1-pentenyl, 5-amino-3-pentenyl, 3-bromo-2-pentenyl, 6- Hydroxy-2-hexenyl and 6-chloro-6-heptenyl and the like.

Examples of the acyl group include alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl, and aroyl groups having 10 or less carbon atoms such as benzoyl. These may have the same substituents as in the case of the substituted alkyl group, and examples of such an acyl group include chloroacetyl, phenylacetyl, trifluoroacetyl, 3-hydroxypropionyl, isobutyryl, 4 -Methoxy-butyryl, isovaleryl, pivaloyl and 12-hydroxylauroyl.

Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
3 carbon atoms such as cycloheptyl and adamantyl
And 10 to 10 cycloalkyl groups.

As the substituted phenyl group, 4-hydroxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4- (dimethylethyl) phenyl, 3-ethylphenyl, or 4-hydroxy-
Hydroxyl groups such as 3,5-bis (dimethylethyl) phenyl,
Examples include an alkoxy group, an alkyl group, and a phenyl group substituted with a halogen atom.

The halogen atom includes fluorine, chlorine, bromine and iodine.

Examples of the alkoxy group include methoxy, ethoxy, propoxy, methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, pentyloxy,
Methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3 -Methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy,
1 carbon atom such as 3,3-dimethylbutoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy
To 6 alkoxy groups.

As the acyloxy group, formyloxy,
1 to 6 carbon atoms such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy and pivaloyloxy
And an aroyloxy group having 10 or less carbon atoms such as benzoyloxy.

Examples of the heterocyclic group include a 5- to 6-membered heteroaromatic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, furyl, thienyl, Examples include pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl and the like.

The ring formed by R ₂ and R ₃ bonded to each other and the carbon atom to which they are bonded may be a 5- to 7-membered saturated or unsaturated carbon atom which may have a substituent. Examples include a hydrogen ring and a nitrogen-containing heterocyclic ring. More specifically, examples of the hydrocarbon ring include a cyclohexane ring and a benzene ring, and examples of the nitrogen-containing heterocyclic ring include 5 or 5 having 1 or 2 nitrogen atoms such as a pyridine ring, a pyrimidine ring, and a pyrrole ring. And a 6-membered nitrogen-containing heterocyclic ring. The ring formed by R ₂ and R ₃ may have a substituent. Examples of such a substituent include a hydroxyl group,
Examples include a halogen atom, an alkyl group, a substituted alkyl group, an alkoxy group, a phenyl group, a substituted phenyl group, an acyl group, a substituted acyl group, an acyloxy group, a nitro group, an amino group, a substituted amino group, and a cyano group. One to four substituents may be substituted on any position of the ring.

The compounds of the present invention may form salts with acids or bases, such as salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, formic acid, acetic acid , Fumaric acid, maleic acid, malic acid, tartaric acid,
Salts with organic carboxylic acids such as aspartic acid or glutamic acid, methanesulfonic acid, benzenesulfonic acid,
salts with sulfonic acids such as p-toluenesulfonic acid, hydroxybenzenesulfonic acid or dihydroxybenzenesulfonic acid, salts with alkali metals such as sodium or potassium, salts with alkaline earth metals such as calcium or magnesium, trimethylamine, triethylamine Or a salt with an organic base such as pyridine or an ammonium salt. The compound of the present invention
It includes stereoisomers and geometric isomers, and further includes all hydrates and crystal forms.

The tumor necrosis factor production or secretion inhibitor of the present invention can be administered orally or parenterally.
That is, it can be orally administered in the form of commonly used dosage forms, for example, tablets, capsules, syrups, suspensions, etc., or injected in the form of solutions, such as solutions, emulsions, suspensions, etc. It can be administered as an agent. It can also be administered rectally in the form of suppositories. Such a dosage form can be produced according to a general method by blending the active ingredient with a usual carrier, excipient, binder, stabilizer and the like. When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like can be added.

The dosage and number of administrations vary depending on symptoms, age, body weight, dosage form and the like. However, for oral administration, usually 10 to 500 mg per day for an adult, and for parenteral administration 1 to 500 mg per day. -100 mg may be administered once or in several divided doses.

The compound of the present invention can be synthesized, for example, by the following production method.

Embedded image

In the above reaction formula, R ₂ , R ₃ , R ₄ ,
A and R ₁₀ represent the same meanings as described above. R ₇ represents a halogen atom, and R ₆ represents a hydrogen atom or a halogen atom (eg, chlorine, bromine, iodine). Q represents a lithium atom or MgX, and X represents a halogen atom such as a chlorine atom and a bromine atom.

Each step in the above reaction formula will be described in detail step by step. Production method 1 is a general method for synthesizing compound (1) of the present invention. A pyridazine derivative (2) which is commercially available, is a known compound, or is obtained in the same manner as the known compound,
The compound (1a) of the present invention can be obtained by reacting with the piperazine derivative (3) in an inert organic solvent while controlling the reaction in the range of 0 ° C to 200 ° C. This reaction also
The reaction may be carried out by mixing a base.

The compound of the present invention represented by the formula (1b) can be produced as follows. i) compounds wherein A is an oxygen atom or an NH group (1b) The compound wherein R ₆ is halogen atom (1a) a compound R ₁₀
Water equivalent to -AH, ammonia water, alcohols,
By reacting with phenols, amines or carboxylic acids in an inert organic solvent in the presence of a base at a temperature in the range of 0 ° C to 200 ° C, the compound of the present invention represented by the target compound (1b) can be obtained. it can.

Ii) Compound (1b) in which A is a single bond Compound (1a) in which R ₆ is a halogen atom has the formula R ₁₀ -Q
(Q represents the same meaning as described above), and the compound of the present invention represented by the target compound (1b) can be obtained by reacting with an organolithium compound represented by the formula (1) or a Grignard reagent.

[0031]

Embedded image Production method 2 is a method for synthesizing a piperazine derivative represented by the formula (3). Piperazine in an inert organic solvent in the presence of a base,
Reaction with the corresponding acyl chloride, carbamoyl chloride and chloroformate in the range of 20 ° C. to 100 ° C. to give the piperazine derivative represented by (3a).

[0032]

Embedded image Production method 3 is another synthesis method of compound (1a). The pyridazine derivative (2) is reacted with an ammonium salt (for example, ammonium chloride, ammonium hydroxide, ammonium acetate, ammonium sulfate, etc.) in an inert organic solvent at a temperature in the range of 0 ° C. to 200 ° C. to obtain (4). . The obtained compound (4) is reacted with a commercially available or known dichloro compound represented by the formula (5) in an inert organic solvent in the presence of a base at a temperature in the range of 0 ° C to 200 ° C to obtain the desired compound (1a). Can be.

(1a) can also be synthesized by Production Method 4.

Embedded image That is, the pyridazine derivative (2) is reacted with piperazine in an inert organic solvent in the presence of a base at a temperature in the range of 0 ° C to 200 ° C to obtain a compound (6). Certain (1a) can be obtained.

Examples of the inert organic solvent used in each of the above reactions include hydrocarbon solvents such as benzene, toluene and hexane, halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane, tetrahydrofuran, diethyl ether, and the like. Ether solvents such as dioxane, dimethylformamide, dimethylsulfoxide,
An aprotic polar solvent such as hexamethylphosphorotriamide can be mentioned, and these can be appropriately selected and used. Examples of the base used in each of the above reactions include tertiary amines (eg, triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaminopyridine, diisopropylethylamine, etc.), and inorganic bases (eg, sodium hydride, hydride Potassium, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, etc.), and organic bases such as butyllithium, lithium diisopropylamide, sodium bistrimethylsilylamide, and sodium methoxide. After completion of the reaction, the target compound is isolated and purified from the reaction mixture by a method generally known in the art, for example, by appropriately selecting and using a solvent extraction, column chromatography, recrystallization and the like. it can.

[0035]

EXAMPLES The present invention will be described below in detail with reference examples and examples, but the present invention is not limited to these examples. In all examples, the free amino compound was dissolved in a dichloromethane solution using a hydrochloric acid / diethyl ether solution (about 7%).
%), And the resulting salt was washed well with diethyl ether and used as the hydrochloride.

Reference Example 1 Phosphorus oxychloride (90.0 ml) was added dropwise to 1-piperazinylphthalazine phthalazone (30.0 g), and the mixture was heated to 100 ° C. After 1 hour, the reaction solution was allowed to cool,
It was poured into ice water (400 ml). The mixture was neutralized with a saturated aqueous solution of potassium carbonate, and the precipitate was collected by filtration. After the precipitate was dried under reduced pressure, it was heated to reflux with xylene (100 ml) together with piperazine (78.5 g). Xylene was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol: triethylamine = 93: 5: 2).

Example 1 1- (4-Floylpiperazine-1
-Il) Phthalazine

Embedded image 1-piperazinylphthalazine (1.00 g) and triethylamine
(3.2 ml) in N, N-dimethylformamide (250 ml)
After cooling to ℃, floyl chloride (0.55 ml) was added and stirred. Then, the solvent was distilled off under reduced pressure, dissolved in a 1: 1 mixed solvent of 1N hydrochloric acid and tetrahydrofuran, and stirred for 1 hour. The organic component was extracted with ethyl acetate, washed with water and brine, and dried (M
gSO ₄ ) and dried under reduced pressure to obtain a solid. Then, the crude product was subjected to silica gel column chromatography (elution solvent, chloroform: ethyl acetate: methanol = 4.5: 5: 0.
5) Purification by 1- (4-furoylpiperazin-1-yl)
Phthalazine (0.72 g) was obtained. mp.198-200 ℃ (hydrochloride)

Examples 2 to 9 The same operation as in Example 1 was performed to obtain the following compounds.

Embedded image

Table 1 Example R Yield (%) Melting point or decomposition point (° C) ───────────────────────────────2 2-thienyl 75 222-224 3 phenyl 86 240-241 4 isopropyl 54 230- 235 5 t-butyl 56 233-235 6 n-C ₁₁ H ₂₃ 78 304-305 7 cyclopentyl 63 235-237 8 cyclohexyl 74 235-237 9 adamantyl 57 296-297 ───────────────────

Example 10 Methyl 4- (1-phthalazinyl) piperazinecarboxylate

Embedded image A solution of 1-piperazinylphthalazine (800 mg) and triethylamine (2.6 ml) in N, N-dimethylformamide (100 ml) was cooled to 0 ° C., and methyl chloroformate (0.43 ml) was added and stirred. Thereafter, the same operation as in Example 1 was performed to obtain methyl 4- (1-phthalazinyl) piperazinecarboxylate (1.00 g, 98%). mp.
229 to 230 ° C (hydrochloride)

Examples 11 to 15 The procedure of Example 1 was repeated, except that the methyl chloroformate in Example 10 was replaced with chloroformates each corresponding to the following R.
By performing the same operation as in Example 0, the following compound was obtained.

Embedded image

Table 2 Example No. R Yield (%) Melting point (° C.) {11 ethyl 66 200-202 12 isobutyl 85 197-198 13 t-butyl 72 305-307 14 allyl 44 129-130} ──────────────────

Reference Example 2 tert-butyl-4-furoylpiperazinecarboxylate tert-butyl-1-piperazinecarboxylate (5.0
g) in anhydrous methylene chloride (50 ml),
Triethylamine (4.07g) and floyl chloride (4.20g)
g) was added. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added, and the organic layer was separated. After the usual treatment, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent, chloroform: methanol = 100: 1) to obtain 7.50 g of tert-butyl-4-furoylpiperazinecarboxylate.

Reference Example 3 1-furoylpiperazine hydrochloride tert-butyl-4-furoylpiperazinecarboxylate (7.50 g) was dissolved in chloroform (30 ml), and 4N HCl / dioxane (10 ml) was added under ice cooling. It was dropped. After completion of the dropwise addition, the temperature was raised to room temperature, and the final solution was stirred. The precipitated crystals were collected by filtration, washed with chloroform, and dried under reduced pressure to obtain 4.36.
g of 1-furoilpiperazine hydrochloride was obtained as a salt. mp. 201.
5 to 202 ° C

Reference Example 4 1-Thenoylpiperazine hydrochloride 1-Tenoylpiperazine hydrochloride was obtained in the same manner as in Reference Examples 2 and 3. mp. 235-236 ° C

Example 15 4-Chloro-1- (4-furoylpiperazin-1-yl) pyridazine

Embedded image 3,6-Dichloropyridazine (1.00 g), 1-furoylpiperazine hydrochloride (1.46 g) and triethylamine (2.75 ml) were dissolved in toluene (30 ml), heated under reflux for 10 hours, and then added with water. The organic component was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (elution solvent, hexane: ethyl acetate = 1:
1) Purification gave 4-chloro-1- (4-furoylpiperazin-1-yl) pyridazine (465 mg).

Example 16 1- (4-Floylpiperazin-1-yl) pyridazine

Embedded image 4-Chloro-1- (4-furoylpiperazin-1-yl) pyridazine (300 mg) was dissolved in THF (20 ml) and 10% palladium-carbon (30 mg) was added. The mixture was stirred vigorously at room temperature under a hydrogen atmosphere. The palladium-carbon was removed by filtration through Celite, the solvent of the filtrate was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel chromatography (developing solvent, hexane: acetone = 1: 1) to give 1-
(4-Floylpiperazin-1-yl) pyridazine (1
53 mg) were obtained. mp. 235 to 236 ° C (hydrochloride)

Example 17 tert-butyl-4- (4-
Chlorophthalazin-1-yl) piperazinecarboxylate

Embedded image 1,4-Dichlorophthalazine (4.00 g), tert-butyl-1-piperazinecarboxylate (4.49 g) and triethylamine (4.0 ml) were dissolved in toluene (100 ml), and the same operation as in Example 15 was performed. -Butyl-
4- (4-Chlorophthalazin-1-yl) piperazinecarboxylate (5.64 g) was obtained. mp. 178-17
9 ° C (free body)

Example 18 tert-butyl-4- (4-
Phenylphthalazin-1-yl) piperazinecarboxylate

Embedded image 1-chloro-4-phenylphthalazine (100 mg), te
rt-butyl-1-piperazinecarboxylate (93 m
g) and triethylamine (0.29 ml) were dissolved in toluene (2 ml), and the same operation as in Example 15 was performed.
rt-Butyl-4- (4-phenylphthalazin-1-yl) piperazinecarboxylate (104 mg) was obtained.
mp. 280-281 ° C (hydrochloride)

Example 19 tert-butyl-4- (4-
Phenoxyphthalazin-1-yl) piperazinecarboxylate

Embedded image Dissolve phenol (130mg) in toluene (3ml)
At room temperature, sodium hydride (70 mg, 60%) was added and stirred. Thereafter, a toluene solution of tert-butyl-4- (4-chlorophthalazin-1-yl) piperazinecarboxylate (400 mg / 1 ml) was added dropwise.
Heated to reflux for 0 hours. After ordinary post-treatment, purification was performed by silica gel column chromatography (eluent, hexane: ethyl acetate = 4: 1), and tert-butyl-4- (4-
Phenoxyphthalazin-1-yl) piperazinecarboxylate (270 mg) was obtained. mp. 270-273 ° C
(Hydrochloride)

Reference Example 5 1-chloro-4-phenoxyphthalazine phenol (1.10 g) was dissolved in toluene (25 ml).
At room temperature, sodium hydride (500 mg, 60%) was added and stirred. Then, the 1,4-dichlorophthalazine D
An MF solution (2.00 g / 40 ml) was added and reacted at room temperature for 6 hours. After normal post-treatment, silica gel column chromatography (eluent, hexane: ethyl acetate =
4: 1) to give 1-chloro-4-phenoxyphthalazine (2.24 g). mp. 132 ° C

Example 20 1- (4-Floylpiperazin-1-yl) -4-phenoxyphthalazine

Embedded image 1-chloro-4-phenoxyphthalazine (500 mg),
1-Froylpiperazine hydrochloride (633 mg) and triethylamine (1.35 ml) were dissolved in DMF (10 ml) and heated under reflux for 10 hours. After usual post-treatment, purification was performed by silica gel column chromatography (eluent, hexane: ethyl acetate = 1: 1), and 1- (4-furoylpiperazin-1-yl) -4-phenoxyphthalazine (260 mg)
I got mp. 116-119 ° C (hydrochloride)

Reference Example 6 5,8-Dichloropyrido [2,3-d] pyridazine pyrido [2,3-d] pyridazine-5,8 (6H, 7
H) Dione (2.50 g) was suspended in phosphorus oxychloride (25 ml), and dimethylaniline (2.5 ml) was added under ice cooling. After stirring at 100 ° C. for 1 hour, the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography (eluate,
Purified with chloroform: methanol = 95: 5),
8-dichloropyrido [2,3-d] pyridazine (1.43
g) was obtained. mp. 167-168 ° C

Example 21 5-Chloro-8- (4-furoylpiperazin-1-yl) pyrido [2,3-d] pyridazine and the 8-chloro isomer

Embedded image 5,8-dichloropyrido [2,3-d] pyridazine (4
27 mg), 1-furoylpiperazine hydrochloride (507 mg)
And triethylamine (474 mg) in ethanol (8 ml)
And heated to reflux for 11 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 99: 1),
5-chloro-8- (4-furoylpiperazin-1-yl) pyrido [2,3-d] pyridazine (498 mg) and its positional isomer 8-chloro-5- (4-furoylpiperazin-1-yl) ) Pyrido [2,3-d] pyridazine (16
7 mg). 5-chloro form: mp. 238-239 ° C
(Hydrochloride)

Example 22 8- (4-Floylpiperazin-1-yl) pyrido [2,3-d] pyridazine

Embedded image 5-chloro-8- (4-furoylpiperazin-1-yl) pyrido [2,3-d] pyridazine (166 mg) was added to 1
Dissolve in 0% aqueous acetic acid (2 ml), and at room temperature, 10% palladium-carbon (80 mg) and ammonium formate (305 mg)
Was added and reacted for 6 hours. After the catalyst was filtered off and the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 97: 3) to give 8- (4-furoylpiperazin-1-yl) pyrido. [2,3-d] pyridazine was obtained. mp. 155-1
56 ° C (hydrochloride)

Example 23 tert-butyl-4- (5-
Chloropyrido [2,3-d] pyridazin-8-yl) piperazinecarboxylate and tert-butyl-4-
(8-chloropyrido [2,3-d] pyridazin-5-yl) piperazinecarboxylate

Embedded image 5,8-dichloropyrido [2,3-d] pyridazine (5
19 mg), tert-butyl-1-piperazinecarboxylate (628 mg) and triethylamine (786 mg) were suspended in ethanol (10 ml), and the same operation as in Example 21 was carried out to give tert-butyl-4- (5-chloropyrido [ 2,3-d] pyridazin-8-yl) piperazinecarboxylate (497 mg) and its positional isomer, tert-butyl-4- (8-chloropyrido [2,3-d] pyridazin-5-yl) piperazinecarboxylate (175m
g) was obtained.

Example 24 tert-Butyl-4- (pyrido [2,3-d] pyridazin-8-yl) piperazinecarboxylate

Embedded image tert-butyl-4- (5-chloropyrido [2,3-d]
Pyridazin-8-yl) piperazine carboxylate (1.67 g), 10% palladium-carbon (500 mg) and ammonium formate (3.01 g) in methanol (100 ml)
And tert-butyl-4- (pyrido [2,3-d] pyridazin-8-yl) piperazinecarboxylate (910 mg) was obtained in the same manner as in Example 22.
mp. 170-173 ° C (hydrochloride)

Example 25 8- (4-thenoylpiperazin-1-yl) pyrido [2,3-d] pyridazine

Embedded image 5,8-dichloropyrido [2,3-d] pyridazine, 1
Example 2 using tenoylpiperazine hydrochloride as a starting material
The same operation as in 1 was performed, and the obtained 5-chloro-
Example 24 using 8- (4-thenoylpiperazin-1-yl) pyrido [2,3-d] pyridazine as a starting material
And the same operation as in 8- (4-thenoylpiperazine-
1-yl) pyrido [2,3-d] pyridazine was obtained. m
p. 235 to 237 ° C (hydrochloride)

Reference Example 7 1,4-Dichloropyrido [3,4-d] pyridazine pyrido [3,4-d] pyridazine-1,4 (2H, 5
H) Dione (13.09 g) was suspended in phosphorus oxychloride (78.5 ml), and pyridine (13 ml) was added under ice cooling. afterwards,
The same operation as in Reference Example 6 was performed to obtain 1,4-dichloropyrido [3,4-d] pyridazine (7.18 g). mp. 1
58-159 ° C

Example 26 4-Chloro-1- (4-thenoylpiperazin-1-yl) pyrido [3,4-d] pyridazine and 1-chloro-4- (4-thenoylpiperazin-1-yl) Pyrido [3,4-d] pyridazine

Embedded image 1,4-dichloropyrido [3,4-d] pyridazine, 1
Example 2 using tenoylpiperazine hydrochloride as a starting material
The same operation as in Example 1 was performed, and 4-chloro-1- (4-thenoylpiperazin-1-yl) pyrido [3,4-d] pyridazine and 1-chloro-4- (4-te), a regioisomer, were obtained. Noylpiperazin-1-yl) pyrido [3,4-d] pyridazine was obtained. 4-chloro form: mp. 241-243 ° C
(Hydrochloride)

Example 27 1- (4-Thenoylpiperazin-1-yl) pyrido [3,4-d] pyridazine

Embedded image 4-chloro-1- (4-thenoylpiperazin-1-yl) pyrido [3,4-d] pyridazine as a starting material,
The same operation as in Example 24 was performed to obtain 1- (4-thenoylpiperazin-1-yl) pyrido [3,4-d] pyridazine. mp. 276.5 to 278 ° C (hydrochloride)

Example 28 4- (4-Thenoylpiperazin-1-yl) pyrido [3,4-d] pyridazine

Embedded image 1-chloro-4- (4-thenoylpiperazin-1-yl) pyrido [3,4-d] pyridazine as a starting material,
The same operation as in Example 24 was performed to obtain 4- (4-thenoylpiperazin-1-yl) pyrido [3,4-d] pyridazine. mp. 265-265.5 ° C (hydrochloride)

Example 29 tert-butyl-4- (pyrido [3,4-d] pyridazin-1-yl) piperazinecarboxylate

Embedded image 1,4-dichloropyrido [3,4-d] pyridazine, te
Using rt-butyl-1-piperazinecarboxylate as a starting material, the same operation as in Example 23 was performed, and the obtained tert-butyl-4- (1-chloropyrido [3,4-
d) Pyridazin-1-yl) piperazinecarboxylate was used as a starting material, and the same operation as in Example 25 was performed.
tert-Butyl-4- (pyrido [3,4-d] pyridazin-1-yl) piperazinecarboxylate was obtained. m
p. 257-258 ° C (hydrochloride)

Example 30 TNF production or secretion inhibition test on mouse peritoneal macrophages Preparation of mouse macrophages BALB / c mice (female, 5-7 weeks old, Charles River) were thioglycollated in a thioglycolate medium (2.4% w / v, Nissui) , Prepared in January 1994) 1 ml was intraperitoneally administered. After raising for 4 days, 4ml of cold MEM
The peritoneal cavity was washed at (Osaka Univ.), And the infiltrated cells in the peritoneal cavity were collected. After washing the cells three times with MEM, add 10% FBS to MEM.
(FBS: Filtron, hereinafter referred to as cMEM). Next, the number of cells was counted by trypan blue staining, and 2 × 106 ce
After adjusting to lls / ml, add 100 to 96-well plate (Corstar).
Seed at μl / well. After incubating the cells at 37 ° C for 1 hour,
After washing twice with EM to remove suspended cells, cMEM was added at 50 μl /
The well-added one was used as a mouse intraperitoneal macrophage in the experiment.・ Induction of TNFα production by LPS stimulation LPS (E. coli o111: B4 LPS, DIFCO, lot 767-427)
Was prepared in cMEM at 1 mg / ml and stored at -20 ° C.
After dilution with M to 20 μg / ml, it was added to the above mouse intraperitoneal macrophages at 100 μl / well. After culturing at 37 ° C for 18 hours, 25 µl of the supernatant was recovered from each well, and TN in the supernatant was collected.
Fα activity was measured. Test compounds dissolved in DMSO to a concentration of 30 mM and stored at 4 ° C. were used in a 10-fold dilution series, and added to the cells at 50 μl / well simultaneously with LPS.・ Measurement of TNFα activity (ELISA method) Anti-TNF antibody (PharMingen, lot 80
26-04 coating buffer ^* adjusted to 2μg / ml) 50μl /
The mixture was added so as to form a well, and allowed to stand at 4 ° C. overnight. wash
After washing twice with buffer (20 ×, 200 μl / well), bl
ock buffer ^** (200 μl / well) was added, and the mixture was allowed to stand at room temperature for 2 hours. Dilute culture supernatant 4 times in plate (25 μl supernatant)
l was added to 75 μl of diluent buffer ^** ). At the same time, a recombinant mouse TNFα (Genzym
e) and a dilution train was prepared and allowed to stand overnight at 4 ° C. After washing four times, a biotinylated anti-TNF antibody (PharMi
ngen, lot 7098-04, adjusted to 1 μg / ml with diluent buffer) to a concentration of 100 μl / well.
Let stand for minutes. After washing 6 times, peroxidase-strept-av
idin (KPL, prepared 1: 1000 with diluent buffer)
The solution was added at a concentration of 00 μl / well, and left at room temperature for 30 minutes. After washing 8 times, TMB microwell peroxidase sub
Strate (KPL) was added at 100 μl / well, and the mixture was allowed to stand at room temperature for 10 minutes. Stop solution ^*** 100μ
l / well, and add the absorbance of each well (A450n
After m) was measured with a microplate reader, data processing was performed using soft-max. TNFα activity is rm-TN
It was quantified by a calibration curve using Fα. TNF of test compound
α production inhibitory activity was determined by the following equation.

TNF production or secretion inhibitory activity (%) =
(1−TNF activity in culture supernatant of compound-added group / TNF activity in culture supernatant of compound-free group) × 100 ^* coating buffer: 0.5 M bicarbonate buffer (pH
8.5) ^** block / diluent buffer: 10% FBS-PBS (-) (FBS
: GIBCO, lot 32P3237, PBS: Takara Shuzo) ^*** stop solution: 1 M phosphoric acid

Table 3 shows the results.

[Table 3] Example Inhibitory activity No.% (30 μM) IC ₅₀ (μM) ──────────────── 1 99 3 2 100 2 3 96 5 4 83 5 56 6 69 18 7 89 11 8 61 9 92 2 10 93 7 11 99 3 12 99 2 13 98 1 14 99 1 16 70 22 17 46 18 58 19 64 20 99 8 21 75 22 78 24 48 25 75 26 43 27 44 28 44 29 47 ───────────────── ───────

Formulation Example 1 Tablets can be produced, for example, by the following method.

[Table 4] Amount (mg / tablet) ──────────────────────────── Ingredient 1 Hydrochloride of the compound of Example 13 10 Ingredient 2 Lactose 72.5 Ingredient 3 Corn starch 30 Ingredient 4 Calcium carboxymethylcellulose 5 component 5 hydroxypropylcellulose (HPC-L) 2 component 6 magnesium stearate 0.5%合計 Total 120mg / tablet ────────────────────────────────── Ingredients 1-4 And granulating using an aqueous solution of the component 5,
Ingredient 6 is added and mixed, and the mixture is tableted to give 120 mg per tablet.
Tablets.

Formulation Example 2 An injection can be produced, for example, as follows.

５ Hydrochloride of the compound of Example 13 10 mg / vial Physiological saline 10 ml / vial溶液 The solution of the above components is sterilized by filtration, filled into a washed and sterilized vial, washed, It can be sealed with a sterilized rubber stopper and wound with a flip-off cap to produce an injection.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/50 ABN A61K 31/50 ABN ACJ ACJ ACS ACS ADA ADA ADP ADP AEB AEB AGZ AGZ C07D 237 / 20 C07D 237/20 237/22 237/22 237/24 237/24 237/30 237/30 405/12 237 405/12 237 409/12 237 409/12 237 471/04 119 471/04 119 // ( (C07D 405/12 237: 20 333: 38) (C07D 409/12 237: 20 333: 38) (C07D 409/12 237: 20 333: 38) (C07D 409/12 237: 30 333: 38)

Claims (5)

[Claims] 1. A compound of the general formula (1) (In the formula, R ₁ represents a halogen atom or a group -A-R _10. A represents a single bond, an oxygen atom or an NH group, and R ₁₀ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl. Represents a group, an acyl group, a substituted acyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group or a monocyclic heterocyclic group, wherein R ₂ and R ₃ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group , A substituted alkyl group, an alkoxy group, a phenyl group, a substituted phenyl group,
Acyl group, substituted acyl group, acyloxy group, nitro group,
It may represent an amino group, a substituted amino group or a cyano group, or R ₂ and R ₃ may combine with each other to form a cyclic structure together with the carbon atom to which they are attached. R
₄ represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a phenyl group, a substituted phenyl group, a cycloalkyl group, an alkoxy group, a phenyloxy group, a substituted phenyloxy group or a heterocyclic group) An inhibitor of tumor necrosis factor production or secretion containing a derivative or a salt thereof. 2. A compound of the general formula (1) (Wherein, .A and R ₁₀ R ₁ represents a halogen atom or a group -A- R _10, A is a single bond, R ₁₀ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl Represents a group, an acyl group, a substituted acyl group, a cycloalkyl group or a monocyclic heterocyclic group, A represents an oxygen atom, and R ₁₀ represents a hydrogen atom, an alkenyl group, a substituted alkenyl group, an acyl group, a substituted acyl group, Represents a cycloalkyl group, a phenyl group, a substituted phenyl group or a monocyclic heterocyclic group, or A represents an NH group, and R ₁₀ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, acyl group, a substituted acyl group, a cycloalkyl group, a phenyl group, each independently .R _2, R ₃ representing a heterocyclic group-substituted phenyl group or a monocyclic, a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group Substituted alkyl group, an alkoxy group, a phenyl group, a substituted phenyl group, an acyl group, a substituted acyl group, an acyloxy group, a nitro group, an amino group, or a substituted amino group, or a cyano group, or, R ₂ and R
₃ are bonded to each other to form a 5- to 7-membered saturated or unsaturated hydrocarbon ring or a nitrogen-containing heterocyclic ring which may have a substituent, together with the carbon atom to which they are bonded. R ₄ is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a phenyl group, a substituted phenyl group,
Cycloalkyl group, alkoxy group, phenyloxy group,
A substituted phenyloxy group or a heterocyclic group) or a salt thereof. 3. R ₂ and R ₃ are bonded together to form a benzene ring or a pyridine ring having a group R ₅ together with the carbon atom to which they are bonded, wherein R ₅ is a hydrogen atom, a hydroxyl group, Halogen atom, alkyl group, substituted alkyl group, alkoxy group, phenyl group, substituted phenyl group, acyl group,
Substituted acyl group, acyloxy group, nitro group, amino group,
The pyridazine derivative or a salt thereof according to claim 2, wherein the pyridazine derivative is a substituted amino group or a cyano group, and R ₅ may be substituted at any position of the benzene ring or the pyridine ring, and the number of substitution is 1 to 4. 4. A ring formed by combining R ₂ and R ₃ with each other is a benzene ring having a group R ₅ , and R ₁ is a group represented by —A—R
Is _10, A is a single bond or an oxygen atom, pyridazine derivative or its salt according to claim 3, wherein R ₁₀ is a hydrogen atom or an alkyl group. 5. The pyridazine derivative or a salt thereof according to claim 3, wherein R ₄ is an alkyl group, an alkoxy group, a phenyloxy group or a heterocyclic group.